Myeloma is almost always associated with extensive bone destruction mediated by osteoclasts. However, bone may not be simply a passive bystander in this disease, but rather act to amplify the growth of myeloma cells in bone. Recent data has suggested to our group the hypothesis that the avidity with which myeloma cells grow in bone compared with other hematologic malignancies is likely influenced by products produced as a consequence of osteoclastic bone resorption, and in particular the cytokine interleukin-6, which is a major growth regulatory factor for myeloma cells. Thus, we propose a vicious cycle may be established between myeloma cells and osteoclastic bone resorption whereby myeloma cells stimulate osteoclasts to resorb bone by the production of osteotropic cytokines such as tumor necrosis factor beta, interleukin-1beta and interleukin-6, but that during the process of osteoclastic bone resorption the cytokine interleukin-6 is generated in prodigious amounts by cells involved in the resorption process and this enhances the growth of myeloma cells in bone. We plan to test this hypothesis in a murine model of myeloma which we have recently characterized which, unlike other animal models of myeloma, mimics the disease in humans by causing osteolytic bone destruction around accumulations of myeloma cells. We plan to determine the cellular sources of osteotropic cytokines in the active bone lesions in this model using immunohistochemistry and in situ hybridization, and to determine the effects of cytokine-mediated osteoclastic bone resorption on myeloma cell behavior using both in vitro and in vivo approaches. Finally, we want to expand preliminary studies in which we have developed an animal model of human myeloma in which hypercalcemia occurs. Our hope is that findings from this study should increase our understanding of the mechanisms by which myeloma cells grow in bone, and potentially lead to new therapeutic approaches for reducing the myeloma cell burden by approaches aimed at inhibiting bone resorption. Chemotherapy for patients with myeloma is not very effective, and new approaches are required. If bone destruction could be prevented in myeloma, this would lead to considerable improvement in life expectancy as well as morbidity in patients with this. devastating bone disease.